Ventricular fibrillation (VF) is the most common cause for sudden death in adults; heart failure patients are particularly prone to VF. The generation of VF requires both a cellular trigger (e.g., action potential prolongation, early and delayed after depolarizations) as well as multi-cellular reentrant events (e.g., spiral wave reentry). Human pluripotent stem cells (PSC) such as hESC can be directed into the cardiac lineage with high efficiency, presenting a potential unlimited source of cardiomyocytes (CMs) for cell-based myocardial repair.
Their functional efficacy and safety, in terms of their arrhythmogenicity, however, have not been thoroughly assessed. Indeed, hESC-CMs are known to be functionally immature at the single-cell level, and as such may serve as substrates for arrhythmias in multi-cellular preparations.
In the native heart, ventricular (V) CMs are aligned in a highly organized manner such that the conduction of electrical signals is anisotropic (i.e. asymmetrical, with distinct transverse and longitudinal velocities) for coordinated, directional electrical and contractile activities. By contrast, hESC-CM clusters differentiated in vitro using either embryoid body (EB) formation or directed. differentiation are randomly organized and isotropic.
There is a need, therefore, to develop technologies to in vitro differentiate pluripotent stem cells into CMs producing more anisotropic electrical signals and having more coordinated, directional electrical and contractile activities.